Package leaflet: Information for the user

Stribild 150 mg/150 mg/200 mg/245 mg film-coated tablets

elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil
Please read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
If you get any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Stribild is and what it is used for
What you need to know before taking Stribild
How to take Stribild
Possible side effects
How to store Stribild
Contents of the pack and other information

1. What Stribild is and what it is used for

Stribild contains four active substances:

elvitegravir, an antiretroviral medicine known as an integrase inhibitor
cobicistat, a medicine that boosts (pharmacokinetic enhancer) the effects of elvitegravir
emtricitabine, an antiretroviral medicine known as a nucleoside reverse transcriptase inhibitor (NRTI)
tenofovir disoproxil, an antiretroviral medicine known as a nucleotide reverse transcriptase inhibitor (NtRTI)

Stribild is a single-tablet regimen for the treatment of human immunodeficiency virus (HIV) infection in adults.
Stribild is also indicated for the treatment of HIV-1 infected adolescents aged 12 to less than 18 years, weighing at least 35 kg, who have previously been treated with other HIV medicines that caused side effects.
Stribild reduces the amount of HIV in your body. This improves your immune system and reduces the risk of developing HIV-related illnesses.

2. What you need to know before taking Stribild

Do not take Stribild

If you are allergic to elvitegravir, cobicistat, emtricitabine, tenofovir, tenofovir disoproxil, or to any of the other ingredients of this medicine (listed in section 6 of this leaflet).
If, on your doctor's advice, you have previously stopped treatment with any medicine containing tenofovir disoproxil due to kidney function problems.
If you are taking any of the following medicines:
- alfuzosin (used to treat prostate gland enlargement)
amiodarone, quinidine (used to correct irregular heartbeats)
dabigatran (a medicine used to prevent and treat blood clots)
carbamazepine, phenobarbital, phenytoin (used to prevent seizures)
rifampicin (used to prevent and treat tuberculosis and other infections)
dihydroergotamine, ergotamine, ergometrine (used to treat migraine)
cisapride (used for certain stomach problems)
St John’s wort (Hypericum perforatum, a herbal remedy used for depression and anxiety) or preparations containing it
lovastatin, simvastatin (used to lower blood cholesterol)
pimozide, lurasidone (used to treat abnormal thoughts or feelings)
sildenafil (used to treat pulmonary arterial hypertension, a lung disease causing breathing difficulties)
midazolam administered orally, triazolam (used to help sleep and/or relieve anxiety)

If any of these conditions apply to you, do not take Stribild and inform your doctor immediately.
Warnings and precautions
While taking Stribild, you must continue to be monitored by your doctor.
This medicine does not cure HIV infection. While taking Stribild, you may still develop infections or other illnesses associated with HIV infection.
Talk to your doctor before taking Stribild:

If you have or have previously had kidney problems, or if blood tests have shown kidney abnormalities. Your doctor will carefully evaluate whether to treat you with Stribild.

Stribild may affect the kidneys. Before starting treatment, your doctor will order blood tests to assess proper kidney function. Your doctor will also order blood tests during treatment to monitor kidney function.
Stribild should not be taken with other medicines that may damage the kidneys (see section Other medicines and Stribild). If this is unavoidable, your doctor will monitor your kidney function more frequently.

If you have osteoporosis, have had bone fractures in the past, or have bone problems.

Bone problems (manifesting as persistent or worsening bone pain and sometimes resulting in fractures) may occur due to damage to renal tubular cells (see section 4, Possible side effects). Inform your doctor if you experience bone pain or fractures.
Tenofovir disoproxil may also cause loss of bone mineral density.
In general, the long-term effects of tenofovir disoproxil on bone health and future fracture risk in adult and paediatric patients are uncertain.

If you have or have previously had liver problems, including hepatitis. Patients with liver problems, including chronic hepatitis B or C, treated with antiretrovirals, have a higher risk of serious liver complications, which may even be fatal. If you have hepatitis B, your doctor will carefully evaluate the best treatment regimen for you.

If you have hepatitis B, liver problems may worsen when you stop treatment with Stribild. It is important that you do not stop treatment with Stribild without speaking to your doctor: see section 3, Do not stop treatment with Stribild.

If you are over 65 years of age. Stribild has not been studied in patients over 65 years of age. If you are over this age and have been prescribed Stribild, your doctor will monitor you closely.

If any of these conditions apply to you, talk to your doctor before taking Stribild.
While taking Stribild
Once you start taking Stribild, be alert for:

any signs of inflammation or infection
bone problems

If you notice any of these symptoms, inform your doctor immediately.
Children and adolescents
Do not give this medicine to children under 12 years of age. The use of Stribild in children under 12 years of age and weighing less than 35 kg has not been studied.
Other medicines and Stribild
Some medicines must never be taken with Stribild.
These are listed in the previous section “Do not take Stribild – If you are taking any of the following medicines”.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicine. Stribild can interact with other medicines. As a result, the blood levels of Stribild or the other medicines may be altered. This may prevent the medicines from working properly or may worsen their side effects. In some cases, your doctor may need to adjust the dose or monitor blood levels.
It is particularly important to talk to your doctor if you are taking any of the following medicines:

any other medicine containing:
- tenofovir disoproxil
- tenofovir alafenamide
- lamivudine
- adefovir dipivoxil
medicines that may damage the kidneys, such as:
- aminoglycosides (e.g. streptomycin, neomycin, gentamicin), vancomycin (for bacterial infections)
- foscarnet, ganciclovir, cidofovir (for viral infections)
- amphotericin B, pentamidine (for fungal infections)
- interleukin-2, also known as aldesleukin (for treating cancer)
- non-steroidal anti-inflammatory drugs (NSAIDs, used to relieve bone or muscle pain)

It is also important to inform your doctor if you are taking any of the following types of medicines:

antifungals, used to treat fungal infections, such as:
- ketoconazole, itraconazole, voriconazole, fluconazole and posaconazole
antivirals, used to treat hepatitis C:
- ledipasvir/sofosbuvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir
antibiotics used to treat bacterial infections, including tuberculosis, containing:
- rifabutin, clarithromycin or telithromycin
antidepressants, used to treat depression:
- medicines containing trazodone or escitalopram
sedatives and hypnotics, used to treat anxiety:
- buspirone, clorazepate, diazepam, estazolam, flurazepam and zolpidem
immunosuppressants, used to control the immune response after transplantation, such as:
- cyclosporine, sirolimus and tacrolimus
corticosteroids, including:
- betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel diseases, inflammatory skin, eye, joint and muscle conditions, and other inflammatory disorders. They are generally taken orally, inhaled, injected, or applied to the skin or eyes. If alternative treatments are not possible, these medicines may only be taken after evaluation by your doctor and under close medical monitoring to detect any corticosteroid-related side effects.
medicines used to treat diabetes:
- metformin
oral contraceptives, used to prevent pregnancy
medicines for erectile dysfunction, used to treat impotence, such as:
- sildenafil, tadalafil and vardenafil
heart medicines, such as:
- digoxin, disopyramide, flecainide, lidocaine, mexiletine, propafenone, metoprolol, timolol, amlodipine, diltiazem, felodipine, nicardipine, nifedipine and verapamil
medicines used to treat pulmonary arterial hypertension:
- bosentan
anticoagulants, used to prevent and treat blood clots, such as:
- warfarin, edoxaban, apixaban and rivaroxaban
bronchodilators, used to treat asthma and other lung disorders:
- salmeterol
cholesterol-lowering medicines, such as:
- rosuvastatin, atorvastatin, pravastatin, fluvastatin and pitavastatin
medicines used to treat gout:
- colchicine
antiplatelet agents, used to reduce the risk of blood clots, such as:
- clopidogrel
oral medicines or supplements containing minerals (such as magnesium, aluminium, calcium, iron, zinc), such as:
- mineral supplements, vitamins (including multivitamins), antacids and laxatives. If you are taking medicines, oral supplements, antacids or laxatives containing minerals (such as magnesium, aluminium, calcium, iron, zinc), take them at least 4 hours before or at least 4 hours after Stribild.

Inform your doctor if you are taking these or any other medicines. Do not stop treatment without contacting your doctor.
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.

Tell your doctor immediately if you are pregnant, think you may be pregnant, or are planning a pregnancy. Pregnant women should not take Stribild. The amount of this medicine in the blood may decrease during pregnancy, which may prevent it from working properly.
Use an effective contraceptive method while taking Stribild.
Do not breastfeed during treatment with Stribild. This is because some of the active substances in this medicine are excreted in human breast milk.
Breastfeeding is not recommended for HIV-positive women because HIV infection can be transmitted to the infant through breast milk.
If you are breastfeeding or considering breastfeeding, you must talk to your doctor as soon as possible.

Driving and using machines
Stribild may cause dizziness, fatigue or insomnia. If you experience these symptoms while taking Stribild, do not drive and do not operate tools or machinery.
Stribild contains lactose
If your doctor has diagnosed you with an intolerance to certain sugars, contact your doctor before taking this medicine.
Stribild contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e. essentially ‘sodium-free’.

3. How to take Stribild

Take this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor or pharmacist.
Recommended dose for adults and adolescents aged 12 to less than 18 years weighing at least 35 kg:

one tablet daily by mouth, taken with food. Do not chew, break, or crush the tablet.

Always take the dose prescribed by your doctor. This is to ensure that your medicine remains fully effective and to reduce the risk of developing resistance to treatment. Do not change the dose unless your doctor tells you to do so.
If you are taking oral medicines, supplements, antacids, or laxatives containing minerals (such as magnesium, aluminium, calcium, iron, zinc), take them at least 4 hours before or at least 4 hours after taking Stribild.
If you take more Stribild than you should
If you accidentally take more Stribild than the recommended dose, you may have an increased risk of experiencing possible side effects of this medicine (see section 4, Possible side effects).
Contact your doctor or the nearest emergency department immediately. Take the bottle of tablets with you so that you can easily describe what you have taken.
If you forget to take Stribild
It is important that you do not miss any doses of Stribild.
If you miss a dose:

and you remember within 18 hours of your usual Stribild dosing time, take the tablet as soon as possible. Always take the tablet with food. Then take your next dose at the usual time.
and you remember after 18 hours or more from your usual Stribild dosing time, do not take the missed dose. Wait and take your next dose with food at the usual time.

If you vomit within 1 hour after taking Stribild, take another tablet with food.
Do not stop treatment with Stribild
Do not stop treatment with Stribild without talking to your doctor. Stopping treatment with Stribild may seriously affect your response to subsequent treatment. If treatment with Stribild is stopped for any reason, talk to your doctor before restarting Stribild tablets.
When your supply of Stribild starts to run low, ask your doctor or pharmacist for a refill. This is very important because the amount of virus may begin to increase if the medicine is interrupted even for a short time. The disease may then become more difficult to treat.
If you have HIV and hepatitis B infection, it is especially important not to stop treatment with Stribild without first talking to your doctor. You may need to have blood tests repeated for several months after stopping treatment. In some patients with advanced liver disease or cirrhosis, stopping treatment is not recommended, as it may lead to worsening of hepatitis, which could be potentially fatal.
Tell your doctor immediately about any new or unusual symptoms you notice after stopping treatment, particularly symptoms usually associated with hepatitis B infection (such as yellowing of the skin or whites of the eyes, dark urine “tea-coloured”, pale stools, loss of appetite for at least several days, feeling sick or vomiting, or stomach pain).
If you have any questions about how to use this medicine, ask your doctor or pharmacist.

4. Possible side effects

During HIV therapy, an increase in weight and in blood levels of lipids and glucose may occur. This is partly related to the recovery of health status and lifestyle, and, in the case of blood lipids, sometimes also to the HIV medicines themselves. Your doctor will monitor these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them. When treating HIV infections, it may not always be possible to determine whether certain side effects are caused by Stribild, by other medicines you are taking at the same time, or by the disease itself.

Possible serious side effects: inform your doctor immediately

Lactic acidosis (excess lactic acid in the blood) is a rare but potentially life-threatening side effect of some HIV medicines. Lactic acidosis occurs more frequently in women, especially if overweight, and in people with liver disease. The following may be signs of lactic acidosis:
- deep, rapid breathing
- tiredness or drowsiness
- feeling unwell (nausea), being sick (vomiting)
- stomach pain If you think you may have lactic acidosis, inform your doctor immediately.
Signs of inflammation or infection. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infections (infections occurring in people with a weakened immune system), signs and symptoms of inflammation from previous infections may appear shortly after starting anti-HIV treatment. These symptoms are thought to result from an improved immune response, enabling the body to fight infections that may have been present without obvious symptoms. In addition to opportunistic infections, autoimmune diseases (a condition in which the immune system attacks healthy body tissue) may also occur when you start taking medicines for the treatment of HIV infection. Autoimmune diseases may occur many months after starting treatment. If you notice any signs of infection or other symptoms such as muscle weakness, weakness starting in the hands and feet and progressing towards the trunk, palpitations, tremors, or hyperactivity, inform your doctor immediately so that you can receive the necessary treatment. If you notice symptoms of inflammation or infection, inform your doctor immediately.

Very common side effects
(may occur in at least 1 out of 10 patients treated)

diarrhoea
vomiting
feeling unwell (nausea)
weakness
headache, dizziness
rash

Blood tests may also show:

reduced phosphate levels in the blood
increased blood creatine kinase levels, which may cause muscle pain and weakness

Common side effects
(may occur in 1 to 10 out of 100 patients treated)

loss of appetite
difficulty sleeping (insomnia), abnormal dreams
pain, stomach ache
digestive problems causing discomfort after meals (dyspepsia)
feeling of abdominal bloating
constipation, intestinal gas (flatulence)
skin rashes (including red spots or pustules, sometimes with blisters and skin swelling), which may be an allergic reaction, itching sensation, skin colour changes with appearance of dark patches
other allergic reactions
tiredness
loss of bone mass

Blood tests may also show:

low white blood cell count (which may make you more susceptible to infection)
increased blood glucose, fatty acids (triglycerides), and bilirubin levels
problems affecting the liver and pancreas
increased blood creatinine levels

Uncommon side effects
(may occur in up to 1 out of 100 patients treated)

suicidal thoughts and suicide attempts (in patients who have previously had depression or mental health problems), depression
back pain caused by kidney problems, including kidney failure. Your doctor may prescribe blood tests to assess whether your kidneys are functioning properly
damage to renal tubular cells
swelling of the face, lips, tongue or throat
abdominal (stomach) pain caused by inflammation of the pancreas (pancreatitis)
muscle breakdown, muscle pain or muscle weakness

Blood tests may also show:

anaemia (low red blood cell count)
reduced potassium levels in the blood
changes in urine

Rare side effects
(may occur in up to 1 out of 1,000 patients treated)

lactic acidosis (see Possible serious side effects: inform your doctor immediately)
yellowing of the skin and eyes, itching sensation or abdominal (stomach) pain caused by liver inflammation (hepatitis)
fatty liver
kidney inflammation (nephritis)
excessive urination and thirst (nephrogenic diabetes insipidus)
softening of the bones (with bone pain and sometimes fractures)

Muscle breakdown, softening of the bones (with bone pain and sometimes fractures), muscle pain, muscle weakness, and decreased potassium or phosphate levels in the blood may occur due to damage to the kidney tubular cells.

If any of the side effects worsen, inform your doctor.

Other possible side effects observed during HIV treatment
The frequency of the following side effects is unknown (frequency cannot be estimated from the available data).

Bone problems. Some patients taking combination antiretroviral medicines such as Stribild may develop a bone disease called osteonecrosis (death of bone tissue caused by reduced blood supply to the bone). Taking this type of medicine for a prolonged period, use of corticosteroids, alcohol consumption, having a weakened immune system, and being overweight may all be among the many risk factors for developing this disease. Signs of osteonecrosis include:
- joint stiffness
- discomfort and pain in the joints (especially hips, knees and shoulders)
- difficulty moving

Other side effects in children

Children treated with emtricitabine very commonly experience skin colour changes, including:
- darkening of the skin in patches
Children commonly experience low red blood cell count (anaemia):
- this may cause tiredness or breathlessness in the child

If you notice any of these symptoms, inform your doctor.

If you get any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist.

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Stribild

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the bottle and carton after {Exp.}. The expiry date refers to the last day of that month.
Store in the original packaging to protect the medicine from moisture. Keep the bottle tightly closed.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Stribild contains
The active substances are elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil. Each film-coated tablet of
Stribild contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine and 245 mg of
tenofovir disoproxil (equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir).
The other components are
Tablet core:
sodium croscarmellose (E468), hydroxypropylcellulose (E463), lactose monohydrate, magnesium stearate (E572), microcrystalline cellulose (E460), silicon dioxide (E551), sodium lauryl sulfate.
Film coating:
indigotine, indigo carmine (E132), macrogol 3350 (E1521), polyvinyl alcohol (partially hydrolysed) (E1203), talc (E553b), titanium dioxide (E171), yellow iron oxide (E172).
Description of the appearance of Stribild and contents of the pack
Stribild film-coated tablets are green, capsule-shaped, marked on one side with “GSI” and on the other side with the number “1” within a square box. Stribild is supplied in bottles containing 30 tablets (with a silica gel desiccant, which must remain in the bottle to protect the tablets). The silica gel is contained in a separate sachet or container and must not be swallowed.
The following pack sizes are available: cardboard boxes containing 1 bottle of 30 film-coated tablets and boxes containing 90 (3 x 30) film-coated tablets. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Gilead Sciences Ireland UC
Carrigtohill
County Cork, T45 DP77
Ireland
Manufacturer
Gilead Sciences Ireland UC
IDA Business & Technology Park
Carrigtohill
County Cork
Ireland
For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien Lietuva
Gilead Sciences Belgium SRL-BV Gilead Sciences Ireland UC
Tél/Tel: + 32 (0) 24 01 35 50 Tel: + 353 (0) 1 686 1888
България Luxembourg/Luxemburg
Gilead Sciences Ireland UC Gilead Sciences Belgium SRL-BV
Тел.: + 353 (0) 1 686 1888 Tél/Tel: + 32 (0) 24 01 35 50
Česká republika Magyarország
Gilead Sciences s.r.o. Gilead Sciences Ireland UC
Tel: + 420 910 871 986 Tel.: + 353 (0) 1 686 1888
Danmark Malta
Gilead Sciences Sweden AB Gilead Sciences Ireland UC
Tlf: + 46 (0) 8 5057 1849 Tel: + 353 (0) 1 686 1888
Deutschland Nederland
Gilead Sciences GmbH Gilead Sciences Netherlands B.V.
Tel: + 49 (0) 89 899890-0 Tel: + 31 (0) 20 718 36 98
Eesti Norge
Gilead Sciences Ireland UC Gilead Sciences Sweden AB
Tel: + 353 (0) 1 686 1888 Tlf: + 46 (0) 8 5057 1849
Ελλάδα Österreich
Gilead Sciences Ελλάς Μ.ΕΠΕ. Gilead Sciences GesmbH
Τηλ: + 30 210 8930 100 Tel: + 43 1 260 830
España Polska
Gilead Sciences, S.L. Gilead Sciences Poland Sp. z o.o.
Tel: + 34 91 378 98 30 Tel.: + 48 22 262 8702
France Portugal
Gilead Sciences Gilead Sciences, Lda.
Tél: + 33 (0) 1 46 09 41 00 Tel: + 351 21 7928790
Hrvatska România
Gilead Sciences Ireland UC Gilead Sciences (GSR) S.R.L
Tel: + 353 (0) 1 686 1888 Tel: + 40 31 631 18 00
Ireland Slovenija
Gilead Sciences Ireland UC Gilead Sciences Ireland UC
Tel: + 353 (0) 214 825 999 Tel: + 353 (0) 1 686 1888
Ísland Slovenská republika
Gilead Sciences Sweden AB Gilead Sciences Slovakia s.r.o
Sími: + 46 (0) 8 5057 1849 Tel: + 421 232 121 210
Italia Suomi/Finland
Gilead Sciences S.r.l. Gilead Sciences Sweden AB
Tel: + 39 02 439201 Puh/Tel: + 46 (0) 8 5057 1849
Κύπρος Sverige
Gilead Sciences Ελλάς Μ.ΕΠΕ. Gilead Sciences Sweden AB
Τηλ: + 30 210 8930 100 Tel: + 46 (0) 8 5057 1849
Latvija United Kingdom (Northern Ireland)
Gilead Sciences Ireland UC Gilead Sciences Ireland UC
Tel: + 353 (0) 1 686 1888 Tel: + 44 (0) 8000 113 700
More detailed information on this medicinal product is available on the website of the European Medicines Agency, http://www.ema.europa.eu/.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION
Scientific conclusions
Taking into account the assessment by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil, the PRAC's scientific conclusions are as follows:
In light of available data on decreased bone mineral density from clinical studies, literature and spontaneous reports, the PRAC considers that a causal relationship between cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil and decreased bone mineral density is at least a reasonable possibility. The PRAC also considers that the current warning/precaution regarding bone effects should be further strengthened. The PRAC concluded that the product information for medicinal products containing cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil should be amended accordingly.
Following review of the PRAC recommendation, the CHMP agrees with the overall conclusions and reasoning for the recommendation.
Reasons for the variation of the terms of the marketing authorisation
Based on the scientific conclusions on cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation.